Coronary artery disease, the major manifestation of atherosclerosis, is the leading cause of death in the Western world. In spite of this striking impact, the pathogenesis of atherosclerosis is till poorly understood. Controversy exists regarding the participation of innate immunity involving macrophages. (Mphi) and natural killer (NK) cells versus antigen-specific acquired immunity involving lymphocytes. Mphi predominate in atherosclerotic lesions. NK cells, although smaller in number a present as well. Furthermore the T lymphocytes that participate in acquired immunity are frequently observed in lesions and have been demonstrated to modulate lesion progression. This proposal will address directly the participation of the innate inflammatory and acquired immune responses in vivo. To demonstrate the participation of NK cells in atherosclerosis resulting from moderate as well as profound hypercholesterolemia, we will combine the use of well characterized mouse models of atherosclerosis with inbred strains of mice that are deficient in T and B cell and / or NK cell function. Our first aim is to detail the frequency and the kinetics of NK cell and T cell localization within lesions of apolipoprotein E-deficient (apo E -/-) and low density lipoprotein receptor-deficient (LDL-R-/-) mice with both moderate and severe hypercholesterolemia. This aim will determine the degree to which NK cells and T lymphocytes influence the progression of ahteroma and reveal whether T and NK cell cytokine expression are responsible for the characteristic pathology of the disease. Because the participation of NK cells will be examined in both immune-competent as well as severely immune-deficient animals, these studies will provide valuable information on the participation of NK cells will be examined in both immune-competent as well as severely immune-deficient animals, these studies will provide valuable information on the participation of both innate and acquired immune responses in atherosclerosis. Our second aim will identify if NK cell and T lymphocyte function within atherosclerotic lesions are influenced by locally produced Mphi apo E. WE have determined that macrophage-derived apo E plays a protective role within the lesions o LDL-r-/- mice and this aim will reveal if regulation of NK cell and/or T cell function is a mechanism by which apo E bestows this protection. The successful completion of these studies will provide critical data about the role of T cells and/or NK cells in arherosclerosis that will aid in the development of new treatment strategies to alter the course of atherosclerosis in humans.